The E3 ubiquitin ligase Rnf8 stabilizes Tpp1 to promote telomere end protection

被引:61
|
作者
Rai, Rekha [1 ]
Li, Ju-Mei [2 ]
Zheng, Hong [3 ]
Lok, Gabriel Tsz-Mei [4 ]
Deng, Yu [5 ]
Huen, Michael S-Y [4 ,6 ]
Chen, Junjie [6 ,7 ]
Jin, Jianping [2 ]
Chang, Sandy [1 ]
机构
[1] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA
[2] Univ Texas Hlth Sci Ctr, Dept Biochem & Mol Biol, Houston, TX USA
[3] Univ Texas Houston, MD Anderson Canc Ctr, Dept Lymphoma Res, Houston, TX 77030 USA
[4] Univ Hong Kong, Genome Stabil Res Lab, Pokfulam, Hong Kong, Peoples R China
[5] Univ Texas Houston, MD Anderson Canc Ctr, Dept Genet, Houston, TX 77030 USA
[6] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06510 USA
[7] Univ Texas Houston, MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA
关键词
DNA-DAMAGE RESPONSE; DEGRADATION; REPAIR; POT1; ACTIVATION; PROTEINS; COMPLEX; BRCA1; UBC13; BETA;
D O I
10.1038/nsmb.2172
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The mammalian shelterin component TPP1 has essential roles in telomere maintenance and, together with POT1, is required for the repression of DNA damage signaling at telomeres. Here we show that in Mus musculus, the E3 ubiquitin ligase Rnf8 localizes to uncapped telomeres and promotes the accumulation of DNA damage proteins 53Bp1 and gamma-H2ax. In the absence of Rnf8, Tpp1 is unstable, resulting in telomere shortening and chromosome fusions through the alternative nonhomologous end-joining (A-NHEJ) repair pathway. The Rnf8 RING-finger domain is essential for Tpp1 stability and retention at telomeres. Rnf8 physically interacts with Tpp1 to generate Ubc13-dependent Lys63 polyubiquitin chains that stabilize Tpp1 at telomeres. The conserved Tpp1 residue Lys233 is important for Rnf8-mediated Tpp1 ubiquitylation and localization to telomeres. Thus, Tpp1 is a newly identified substrate for Rnf8, indicating a previously unrecognized role for Rnf8 in telomere end protection.
引用
收藏
页码:1400 / U121
页数:9
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